In the context of the treatment of HIV/AIDS, many improvements have been achieved since the intro... more In the context of the treatment of HIV/AIDS, many improvements have been achieved since the introduction of the combination therapy (HAART). Nevertheless, no cure for this disease has been so far possible, because of some particular features of the therapies. Among them, two important ones have been selected and will be the subject of this review. The first main concern in the treatments is the poor drug bioavailability, resulting in repeated administrations and therefore a demanding compliance (drug regimens consist of multiple drugs daily intake, and non-adherence to therapy is among the important reasons for treatment failure). A second important challenge is the need to target the drugs into the so-called reservoirs and sanctuaries, i.e. cells or body compartments where drugs cannot penetrate or are distributed in sub-active concentrations. The lack of antiviral action in these regions allows the virus to lie latent and start to replicate at any moment after therapy suspension. Recent drug delivery strategies addressing these two limitations will be presented in this review. In the first part, strategies to improve the bioavailability are proposed in order to overcome the absorption or the target cell barrier, or to extend the efficacy time of drugs. In the second section, the biodistribution issues are considered in order to target the drugs into the reservoirs and the sanctuaries, in particular the mononuclear phagocyte system and the brain.
Chitosan (CS) nanoparticles are typically obtained by complexation with tripolyphosphate (TPP) io... more Chitosan (CS) nanoparticles are typically obtained by complexation with tripolyphosphate (TPP) ions, or more recently using triphosphate group-containing drugs such as adenosine triphosphate (ATP). ATP is an active molecule we aim to deliver in order to restore its depletion in macrophages, when associated with their death leading to plaque rupture in atherosclerotic lesions. Despite high interest in CS nanoparticles for drug delivery, due to the biodegradability of CS and to the ease of the preparation process, these systems tend to readily disintegrate when diluted in physiological media. Some stabilization strategies have been proposed so far but they typically involve the addition of a coating agent or chemical cross-linkers. In this study, we propose the complexation of CS with iron ions prior to nanoparticle formation as a strategy to improve the carrier stability. This can be achieved thanks to the ability of iron to strongly bind both chitosan and phosphate groups. Nanoparticles were obtained from either TPP or ATP and chitosan-iron (CS-Fe) complexes containing 3 to 12% w/w iron. Isothermal titration calorimetry showed that the binding affinity of TPP and ATP to CS-Fe increased with the iron content of CS-Fe complexes. The stability of these nanoparticles in physiological conditions was evaluated by turbidity and by fluorescence fluctuation in real time upon dilution by electrolytes, and revealed an important stabilization effect of CS-Fe compared to CS, increasing with the iron content. Furthermore, in vitro studies on two macrophage cell lines (J774A.1 and THP-1) revealed that ATP uptake is improved consistently with the iron content of CS-Fe/ATP nanoparticles, and correlated to their lower dissociation in biological medium, allowing interesting perspectives for the intracellular delivery of ATP.
Nucleoside analogues display significant anticancer or antiviral activity by interfering with DNA... more Nucleoside analogues display significant anticancer or antiviral activity by interfering with DNA synthesis. However, there are some serious restrictions to their use, including their rapid metabolism and the induction of resistance. We have discovered that the linkage of nucleoside analogues to squalene leads to amphiphilic molecules that self-organize in water as nanoassemblies of 100-300 nm, irrespective of the nucleoside analogue used. The squalenoyl gemcitabine exhibited superior anticancer activity in vitro in human cancer cells and gemcitabine-resistant murine leukemia cells, and in vivo in experimental leukemia both after intravenous and oral administration. The squalenoylation of other antiretroviral nucleosides also led to more potent drugs when tested in primary cultures of HIV-infected lymphocytes. Thus, the squalenoylation is an original technology platform for generating more potent anticancer and antiviral nanomedicines.
Nucleoside analogues, together with nucleobases and nucleotide analogues, are commonly used in th... more Nucleoside analogues, together with nucleobases and nucleotide analogues, are commonly used in the treatment of cancer and viral infections. In both cases, they act as antimetabolite agents and interfere with the synthesis of cellular or viral nucleic acids. However, the need of high doses due to the rapid elimination of these compounds, to their poor activation, and/or to their non-specific distribution, often leads to side effects and resistances. The present paper aims to review the different types of polymer nanoparticles which have been designed as drug delivery devices to address these issues. Thus, poly(alkylcyanoacrylate) nanoparticles have been demonstrated as potential carriers for antiviral nucleoside analogues, especially for anti-HIV agents, regarding both intravenous and oral routes. Nanoparticles based on polyesters such as poly(lactic acid) and poly(lactide-co-glycolide) have been used as nanocarriers for nucleosides analogues too, and especially for their ocular delivery. Albumin has shown interesting properties in the design of nanoparticles for the same application, but also for the oral administration of anticancer analogues. Finally, new hydrophilic nanoparticles consisting of cross-linked polymer network ('Nanogels') open the perspective to deliver nucleoside analogues within their active triphosphate form.
Specific siRNAs that target estrogen receptor alpha (ERalpha) were encapsulated in nanocapsules (... more Specific siRNAs that target estrogen receptor alpha (ERalpha) were encapsulated in nanocapsules (NCs). We produced small (approximately 100-200 nm) ERalpha-siRNA NCs with a water core by incorporating two mixed duplexes of specific ERalpha-siRNAs (ERalpha-mix-siRNA) into NCs. The encapsulation yield that was obtained with poly(iso-butylcyanoacrylate) (PIBCA) NCs was low, whereas no release of trapped siRNA was observed for poly(ethylene)glycol-poly(D,L-lactide-co-glycolide) (PEG-PLGA) NCs. High levels of ERalpha-siRNA incorporation into PEG-epsilon-caprolactone-malic acid (PEG-PCL/MA) NCs (3.3 microM in a polymer solution at 16 mg/mL) were observed (72% yield). No difference in size or zeta potential was observed between siRNA NCs that were based on PEG-PCL/MA and empty NCs. Fluorescence quenching assays confirmed the incorporation of siRNA into the NC core. A persistent loss of ERalpha (90% over 5 days) was observed in MCF-7 human breast cancer cells that were exposed to PEG-PCL/MA NCs that were loaded with ERalpha-siRNA. The intravenous injection of these NCs into estradiol-stimulated MCF-7 cell xenografts led to a significant decrease in tumor growth and a decrease in ERalpha expression in tumor cells. These data indicate that a novel strategy, based on ERalpha-siRNA delivery, could be developed for the treatment of hormone-dependent breast cancers.
In the context of the treatment of HIV/AIDS, many improvements have been achieved since the intro... more In the context of the treatment of HIV/AIDS, many improvements have been achieved since the introduction of the combination therapy (HAART). Nevertheless, no cure for this disease has been so far possible, because of some particular features of the therapies. Among them, two important ones have been selected and will be the subject of this review. The first main concern in the treatments is the poor drug bioavailability, resulting in repeated administrations and therefore a demanding compliance (drug regimens consist of multiple drugs daily intake, and non-adherence to therapy is among the important reasons for treatment failure). A second important challenge is the need to target the drugs into the so-called reservoirs and sanctuaries, i.e. cells or body compartments where drugs cannot penetrate or are distributed in sub-active concentrations. The lack of antiviral action in these regions allows the virus to lie latent and start to replicate at any moment after therapy suspension. Recent drug delivery strategies addressing these two limitations will be presented in this review. In the first part, strategies to improve the bioavailability are proposed in order to overcome the absorption or the target cell barrier, or to extend the efficacy time of drugs. In the second section, the biodistribution issues are considered in order to target the drugs into the reservoirs and the sanctuaries, in particular the mononuclear phagocyte system and the brain.
Chitosan (CS) nanoparticles are typically obtained by complexation with tripolyphosphate (TPP) io... more Chitosan (CS) nanoparticles are typically obtained by complexation with tripolyphosphate (TPP) ions, or more recently using triphosphate group-containing drugs such as adenosine triphosphate (ATP). ATP is an active molecule we aim to deliver in order to restore its depletion in macrophages, when associated with their death leading to plaque rupture in atherosclerotic lesions. Despite high interest in CS nanoparticles for drug delivery, due to the biodegradability of CS and to the ease of the preparation process, these systems tend to readily disintegrate when diluted in physiological media. Some stabilization strategies have been proposed so far but they typically involve the addition of a coating agent or chemical cross-linkers. In this study, we propose the complexation of CS with iron ions prior to nanoparticle formation as a strategy to improve the carrier stability. This can be achieved thanks to the ability of iron to strongly bind both chitosan and phosphate groups. Nanoparticles were obtained from either TPP or ATP and chitosan-iron (CS-Fe) complexes containing 3 to 12% w/w iron. Isothermal titration calorimetry showed that the binding affinity of TPP and ATP to CS-Fe increased with the iron content of CS-Fe complexes. The stability of these nanoparticles in physiological conditions was evaluated by turbidity and by fluorescence fluctuation in real time upon dilution by electrolytes, and revealed an important stabilization effect of CS-Fe compared to CS, increasing with the iron content. Furthermore, in vitro studies on two macrophage cell lines (J774A.1 and THP-1) revealed that ATP uptake is improved consistently with the iron content of CS-Fe/ATP nanoparticles, and correlated to their lower dissociation in biological medium, allowing interesting perspectives for the intracellular delivery of ATP.
Nucleoside analogues display significant anticancer or antiviral activity by interfering with DNA... more Nucleoside analogues display significant anticancer or antiviral activity by interfering with DNA synthesis. However, there are some serious restrictions to their use, including their rapid metabolism and the induction of resistance. We have discovered that the linkage of nucleoside analogues to squalene leads to amphiphilic molecules that self-organize in water as nanoassemblies of 100-300 nm, irrespective of the nucleoside analogue used. The squalenoyl gemcitabine exhibited superior anticancer activity in vitro in human cancer cells and gemcitabine-resistant murine leukemia cells, and in vivo in experimental leukemia both after intravenous and oral administration. The squalenoylation of other antiretroviral nucleosides also led to more potent drugs when tested in primary cultures of HIV-infected lymphocytes. Thus, the squalenoylation is an original technology platform for generating more potent anticancer and antiviral nanomedicines.
Nucleoside analogues, together with nucleobases and nucleotide analogues, are commonly used in th... more Nucleoside analogues, together with nucleobases and nucleotide analogues, are commonly used in the treatment of cancer and viral infections. In both cases, they act as antimetabolite agents and interfere with the synthesis of cellular or viral nucleic acids. However, the need of high doses due to the rapid elimination of these compounds, to their poor activation, and/or to their non-specific distribution, often leads to side effects and resistances. The present paper aims to review the different types of polymer nanoparticles which have been designed as drug delivery devices to address these issues. Thus, poly(alkylcyanoacrylate) nanoparticles have been demonstrated as potential carriers for antiviral nucleoside analogues, especially for anti-HIV agents, regarding both intravenous and oral routes. Nanoparticles based on polyesters such as poly(lactic acid) and poly(lactide-co-glycolide) have been used as nanocarriers for nucleosides analogues too, and especially for their ocular delivery. Albumin has shown interesting properties in the design of nanoparticles for the same application, but also for the oral administration of anticancer analogues. Finally, new hydrophilic nanoparticles consisting of cross-linked polymer network ('Nanogels') open the perspective to deliver nucleoside analogues within their active triphosphate form.
Specific siRNAs that target estrogen receptor alpha (ERalpha) were encapsulated in nanocapsules (... more Specific siRNAs that target estrogen receptor alpha (ERalpha) were encapsulated in nanocapsules (NCs). We produced small (approximately 100-200 nm) ERalpha-siRNA NCs with a water core by incorporating two mixed duplexes of specific ERalpha-siRNAs (ERalpha-mix-siRNA) into NCs. The encapsulation yield that was obtained with poly(iso-butylcyanoacrylate) (PIBCA) NCs was low, whereas no release of trapped siRNA was observed for poly(ethylene)glycol-poly(D,L-lactide-co-glycolide) (PEG-PLGA) NCs. High levels of ERalpha-siRNA incorporation into PEG-epsilon-caprolactone-malic acid (PEG-PCL/MA) NCs (3.3 microM in a polymer solution at 16 mg/mL) were observed (72% yield). No difference in size or zeta potential was observed between siRNA NCs that were based on PEG-PCL/MA and empty NCs. Fluorescence quenching assays confirmed the incorporation of siRNA into the NC core. A persistent loss of ERalpha (90% over 5 days) was observed in MCF-7 human breast cancer cells that were exposed to PEG-PCL/MA NCs that were loaded with ERalpha-siRNA. The intravenous injection of these NCs into estradiol-stimulated MCF-7 cell xenografts led to a significant decrease in tumor growth and a decrease in ERalpha expression in tumor cells. These data indicate that a novel strategy, based on ERalpha-siRNA delivery, could be developed for the treatment of hormone-dependent breast cancers.
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Papers by Hervé Hillaireau